A variety of common clinical bladder disorders are characterized by spastic or hyperactive bladder smooth muscle, and the ability to store only small quantities of urine. These dysfunctions range from severe hyperactivity, seen following recovery from major spinal cord damage or spinal transection, to mild bladder detrusor hyperactivity, seen in large numbers of patients and due to a variety of causative factors. The causative factors for this latter group of patients include Parkinsonism, multiple sclerosis, cerebrovascular damage, cerebral arteriosclerosis, central nervous system lesions, and a recurrent bladder infection. The major symptoms of these patients are: frequency, nocturia, urgency, and urge incontinence. The treatment of these patients is generally directed to facilitating urine storage by inhibiting bladder contractility or increasing outlet resistance by enhancing sphincter activity.
Pharmacologic management is usually the first type of treatment attempted. A variety of pharmacologic agents have been used to treat these patients, including muscarinic anticholinergics, tricyclic antidepressants, calcium antagonists, .beta.-andrenergic agonists, and prostaglandin inhibitors. Anticholinergic agents, such as propantheline, oxybutynin, or dicyclomine, alone or in combination with a tricyclic antidepressant, such as imipramine, have proven useful in some patients with bladder hyperactivity. However, nearly 50% of these patients have little or no response to present pharmacological therapies. The consequences of therapeutic failure are costly, and often require serious surgical procedures, such as bladder over-distension, peripheral bladder denervation, or selective sacral rhizotomy. The need for novel pharmacologic approaches for management of these patients is generally agreed upon by urologists.
Incontinence is divided into two types, urge and stress. The urge incontinence type has been further divided into two subtypes in the classical literature, motor urge incontinence and sensory urge incontinence. Motor urge incontinence implies that there is excessive excitatory efferent input to the sacral spinal micturition center from supraspinal centers. Motor urge incontinence accompanies Parkinsonism, multiple sclerosis, cerebrovascular damage, cerebral arteriosclerosis, and central nervous system lesions. Sensory urge incontinence implies excessive sensory input to the sacral spinal micturition center from the bladder primary afferent fibers. Sensory urge incontinence typically accompanies spinal cord injury and bladder infection.
The excitatory amino acids are an important group of neurotransmitters that mediate excitatory neurotransmission in the central nervous system. Glutamic acid and aspartic acid are two endogenous ligands that activate excitatory amino acid (EAA) receptors. There are two types of EAA receptors, ionotropic and metabotropic, which differ in their mode of signal transduction. There are at least three distinct ionotropic EAA receptors characterized by the selective agonist that activate each type: the NMDA (N -methyl-D-aspartic acid), the AMPA (2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid), and the kainic acid receptors. The ionotropic EAA receptors are linked to ion channels that are permeable to sodium, and, in the case of NMDA receptors, calcium. Metabotropic receptors, linked to phosphoinositide-hydrolysis by a membrane associated G-protein, are activated by quisqualic acid, ibotenic acid, and (1S,3R)-1-aminocyclopentane 1,3-dicarboxylic acid.
The NMDA receptor is a macromolecular complex consisting of a number of distinct binding sites that gate an ion channel permeable to sodium and calcium ions. Hansen and Krogsgaard-Larsen, Med. Res. Rev., 10, 55-94 (1990). There are binding sites for glutamic acid, glycine, and polyamines, and a site inside the ion channel where compounds such as phencyclidine (PCP) and MK-801 exert their antagonist effects.
Competitive NMDA antagonists are compounds which block the NMDA receptor by interacting with the glutamate binding site. The ability of a particular compound to competitively bind to the NMDA glutamate receptor is determined using a radioligand binding assay. See Murphy et al., British J. Pharmacol., 95, 932-938 (1988). The antagonists are distinguished from the agonists using a rat cortical wedge assay. See Harrison and Simmonds, British J. Pharmacol., 84, 381-391 (1984). Examples of competitive NMDA antagonists include D-2 amino 5-phosphonopentanoic acid (D-AP5), D-2-amino-7-phosphonoheptanoic acid (D-AP7), CGS19775, CPPene, and CGP37849. Schoepp et al., J. Neur. Transm., 85, 131-143 (1991).
Antagonists of neurotransmission at NMDA receptors may prove to be useful therapeutic agents for the treatment of neurological disorders. U.S. Pat. No. 4,902,695 is directed to series of competitive NMDA antagonists useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders such as Alzheimer's disease and Huntington s disease. U.S. Pat. No. 4,968,878 is directed to a second series of competitive NMDA receptor antagonists useful for the treatment of similar neurological disorders and neurodegenerative disorders.
Bladder activity is controlled by parasympathetic preganglionic neurons in the sacral spinal cord. DeGroat et al., J. Auton. Nerv. Sys., 3, 135-160 (1981). In humans, it has been shown that the highest density of NMDA receptors in the spinal cord are located at the sacral level, including those areas that putatively contain bladder parasympathetic preganglionic neurons. Shaw et al., Brain Res., 539, 164-168 (1991). Because NMDA receptors are excitatory in nature, pharmacological blockade of these receptors would suppress bladder activity. Recent studies have shown that MK-801, a non-competitive NMDA antagonist, increases the volume necessary to elicit micturition and decreases the amplitude of the micturition contraction. Maggie et al., Eur. J. Pharmacol, 181, 105-109 (1990); Yoshiyama et al., Neurosci. Lett., 126, 141-144 (1991). However, these studies have shown that the inhibitory effects of MK-801 are not stereospecific, suggesting that non-specific effects of MK-801 mediated the bladder inhibition. Also, these studies have shown that MK-801 produces endocrine effects that are dissociated from its NMDA antagonism. A separate study has shown that the administration of MK-801 to conscious, freely-moving rats produces an increase in the frequency of micturition. Vera and Nadelhaft, Neurosci. Lett., 134, 135-138 (1991).